U.S. patent number 8,246,986 [Application Number 10/950,003] was granted by the patent office on 2012-08-21 for drug coating providing high drug loading.
This patent grant is currently assigned to Alza Corporation. Invention is credited to Ryan Bronz, Evangeline Cruz, David Edgren, Tracy Fink, Carmelita Garcia, Sherry Li, Brenda Pollock, Gregory Ruhlmann, Alfredo M. Wong.
United States Patent |
8,246,986 |
Cruz , et al. |
August 21, 2012 |
Drug coating providing high drug loading
Abstract
Aqueous drug coatings including at least one insoluble drug,
wherein the insoluble drug accounts for about 85 wt % to about 97
wt % of the drug coatings are described. Such drug coatings may
include only one insoluble drug, two or more insoluble drugs, or
one or more insoluble drugs in combination with one or more soluble
drugs.
Inventors: |
Cruz; Evangeline (Hayward,
CA), Ruhlmann; Gregory (Cupertino, CA), Pollock;
Brenda (Cupertino, CA), Li; Sherry (Cupertino, CA),
Garcia; Carmelita (Newark, CA), Wong; Alfredo M.
(Sunnyvale, CA), Bronz; Ryan (Cupertino, CA), Fink;
Tracy (Campbell, CA), Edgren; David (Los Altos, CA) |
Assignee: |
Alza Corporation (Vacaville,
CA)
|
Family
ID: |
34825863 |
Appl.
No.: |
10/950,003 |
Filed: |
September 23, 2004 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20050112195 A1 |
May 26, 2005 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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60506195 |
Sep 26, 2003 |
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Current U.S.
Class: |
424/464; 424/468;
424/458; 424/472 |
Current CPC
Class: |
A61K
9/1676 (20130101); A61K 31/167 (20130101); A61K
9/2886 (20130101); A61K 9/209 (20130101); A61K
9/4808 (20130101); A61K 9/0004 (20130101); A61K
31/00 (20130101); A61K 31/165 (20130101); A61P
29/00 (20180101); A61P 25/04 (20180101); A61K
31/485 (20130101); A61K 31/165 (20130101); A61K
2300/00 (20130101); A61K 31/167 (20130101); A61K
2300/00 (20130101); A61K 31/485 (20130101); A61K
2300/00 (20130101); A61K 9/2086 (20130101); A61K
9/5084 (20130101) |
Current International
Class: |
A61K
9/24 (20060101); A61K 9/22 (20060101); A61K
9/54 (20060101) |
Field of
Search: |
;424/464,468,472
;514/282 |
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|
Primary Examiner: Wax; Robert A
Assistant Examiner: Palenik; Jeffrey T
Attorney, Agent or Firm: Kais; Samuel M.
Parent Case Text
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims benefit of U.S. Provisional Patent
application No. 60/506,195, filed Sep. 26, 2003, which is
incorporated herein by reference.
Claims
What is claimed is:
1. A dosage form comprising: an osmotic core comprising
hydrocodone; a coating comprising acetaminophen, a viscosity
enhancer, a water soluble film former comprising copovidone and
hydroxypropyl methylcellulose in a wt/wt ratio of between 0.6:1 to
0.7:1, and an excipient selected from the group consisting of a
surfactant and a disintegrating agent; and an intervening layer
between the osmotic core and the coating; wherein the acetaminophen
is present in the coating in an amount ranging from about 60 wt %
to about 97 wt % based on the total weight of the coating, the
viscosity enhancer accounts for about 5 wt % or less based on said
total weight, the excipient accounts for about 0.5 wt % to about 3
wt % based on said total weight, and the water soluble film former
accounts for about 3 wt % to about 15 wt % based on said total
weight.
2. The dosage form of claim 1, wherein acetaminophen is present in
the coating in an amount ranging from about 85 wt % to about 97 wt
%, based on the total weight of the coating.
3. The dosage form of claim 1, wherein the acetaminophen is present
in the coating in an amount ranging from about 75 wt % to about
89.5 wt %, based on the total weight of the coating.
4. The dosage form of claim 1, wherein the wt/wt ratio of
copovidone to hydroxypropyl methylcellulose is about 1:1.5.
Description
BACKGROUND
1. Field of the Invention
The present invention relates to drug coatings that can be formed
within or over dosage forms to deliver one or more insoluble or
soluble drugs. In particular, the present invention provides drug
coatings, coating formulations and methods that provide
aqueous-based drug coatings that exhibit high loading of at least
one insoluble drug, can be loaded with one or more insoluble drugs
in combination with one or more insoluble drugs, and may be applied
to a variety of different dosage forms.
2. State of the Art
Drug coatings are known in the art. For example, U.S. Pat. Nos.
4,576,604, 4,717,569, 4,763,405, 5,273,760, 5,286,493, 5,407,686,
5,998,478, 6,004,582 and 6,136,345, the contents of each of which
are incorporated herein in their entirety by reference, teach
various different drug coating formulations designed to provide the
immediate release of one or more drugs of interest. In addition,
International Applications numbered WO 96/10996, WO 99/55313, WO
00/35426 and WO 01/51038, the contents of which are incorporated
herein in their entirety by reference, also teach various different
drug coating formulations that may be provided over various
different dosage forms. Drug coatings that can be coated over
dosage forms are useful for a variety of reasons. In particular,
the use of a drug-containing overcoat can impart multiple
performance characteristics to a single dosage form. For example, a
dosage form providing the controlled release of one or more drugs
can be coated with an immediate release drug overcoat to provide a
dosage form that combines the benefits of an immediate release
dosage form with the benefits of a controlled release dosage
form.
Where a coating formulation is to be used to provide a drug coating
over or within a dosage form, the coating formulation should
provide drug loading characteristics that permit therapeutic dosing
of the drug incorporated in the coating, while maintaining
desirable coating characteristics. The loading characteristics of a
drug coating become especially important as the desired dose of
drug to be delivered from the drug coating increases. As the
required dose increases, the drug loading performance of the drug
coating formulation must also increase. If the drug coating
formulation does not exhibit sufficient drug loading, the thickness
of a coating required to deliver a desired dose of drug may
increase to such an extent that manufacturing, cosmetic, and
patient compliance issues may be encountered.
Moreover, although, drug coatings can be prepared from organic
solvents or solvent systems containing one or more organic
solvents, the use of organic solvents presents several potential
disadvantages. Organic solvents are relatively costly, often
volatile, are potentially harmful to the environment, and create
potential health hazards for workers. Because of the potential harm
organic solvents present to workers and the environment, the use of
organic solvents in a manufacturing process typically creates
various regulatory hurdles that must be overcome. Moreover, where
organic solvents are used to produce drug coatings, some residual
amount of solvent may remain in the finished coating, which,
depending on the amount and the solvent used, may be harmful to an
intended subject. In light of the potential disadvantages presented
by organic solvents, it is generally preferred to formulate drug
coatings and coating compositions using solvents or solvent systems
that do not include organic solvents.
In particular, where possible, it is typically preferable to
formulate drug coatings using an aqueous solvent, such as purified
water. It would be desirable, therefore, to provide a drug coating
that not only can be coated from an aqueous coating composition,
but also exhibits drug loading capabilities that facilitate
delivery of a wide range of drug doses from coatings having
physical and aesthetic characteristics suitable for commercial
production. Ideally, such a drug coatings could be formulated to
include high concentrations of even water insoluble drugs, or
combinations of one or more water insoluble drugs with one or more
water soluble drugs.
SUMMARY OF THE INVENTION
In one aspect, the present invention is directed to an aqueous drug
coating. As it is used herein, the term "aqueous drug coating"
refers to a water soluble or water erodible coating formed from a
coating formulation that is free from organic solvent. A drug
coating according to the present invention can be created from an
aqueous coating formulation and includes at least one insoluble
drug and a film-forming agent. As they are used herein, the term
"drug" includes medicines, active agents, therapeutic compounds,
therapeutic proteins, therapeutic peptides, nutrients, vitamins,
food supplements, and any other agents that are beneficial to an
intended subject, the term "insoluble" indicates drugs having a
solubility in water that is less than 50 mg/ml at 25.degree. C.,
with drugs having a solubility in water of 8-10 mg/ml at 25.degree.
C. being preferred, and drugs having a solubility in water of less
than 1 mg/ml at 25.degree. C. being particularly preferred. The
drug coating according to the present invention includes from about
85 wt % to about 97 wt % drug, with preferred embodiments providing
a drug loading of about 90 wt % to about 93 wt %.
Though each embodiment of the drug coating of the present invention
includes at least one insoluble drug, the drug coating of the
present invention is also embodied by drug coatings that include
two or more insoluble drugs or one or more insoluble drugs in
combination with one or more soluble drugs. As it is used herein,
the term "soluble" indicates drugs having a solubility in water
that is 50 mg/ml or greater at 25.degree. C. Where the drug coating
of the present invention includes more than one drug, the different
drugs may be included in the drug coating at a ratio that provides
a desired therapeutic effect. Moreover, the formulation of a drug
coating of the present invention not only allows the loading of two
or more drugs have different solubilities, but following
administration to an environment of operation, a drug coating of
the present invention permits proportional delivery of the two or
more drugs included therein.
In another embodiment, the drug coating according to the present
invention includes a viscosity enhancer. As it is used herein, the
term "viscosity enhancer" refers to a material that can be included
in a composition for forming a drug coating of the present
invention that is both water soluble and works to increase the
viscosity of the coating composition. Depending on the relative
amounts and nature of the film forming agent and the one or more
drugs included in a drug coating of the present invention,
incorporation of a viscosity enhancer in a drug coating according
to the present invention may better facilitate production of a drug
coating that exhibits substantially uniform distribution of
drug.
In further embodiments, the drug coating of the present invention
may also include a surfactant or a disintegrating agent. The term
"surfactant" refers to material that is works to reduce the surface
tension of aqueous liquids such that an aqueous liquid can more
easily spread across and penetrate the materials forming a drug
coating according to the present invention, and the term
"disintegrating agent" refers to a water swellable material that
works to structurally compromise a coating of the present invention
as the disintegrating agent absorbs water and swells. In each
embodiment, the drug coating according to the present invention
provides relatively high drug loading, and in each embodiment, the
drug coating according to the present invention includes at least
one insoluble drug. Therefore, a surfactant or disintegrating agent
may be included in a drug coating of the present invention to
facilitate break down or dissolution of the drug coating after
administration to an environment of operation and thereby increase
the rate at which the drug included in the drug coating is
released.
In another aspect the, the present invention is directed to a drug
coating formulation. A coating formulation according to the present
invention is an aqueous composition, preferably formed using
purified water as the solvent. The coating composition of the
present invention is formulated to allow coating of a drug coating
according to the present invention, and in each embodiment, the
coating formulation of the present invention includes at least one
insoluble drug. As the coating formulation of the present invention
is an aqueous formulation that includes at least one insoluble
drug, the coating formulation of the present invention will
typically be formed as a dispersion, with coating formulations
exhibiting a substantially uniform dispersion of insoluble drug
being preferred. The coating composition according to the present
invention may be formulated to facilitate spray coating of a drug
coating of the present invention, and typically includes a solids
content ranging up to 30 wt %, with coating compositions having a
solids content ranging from about 5 wt % to about 25 wt % being
preferred, and coating compositions having a solids content ranging
from about 10 wt % to about 20 wt % being particularly
preferred.
In yet another aspect, the present invention is directed to a
dosage form. A dosage form according to the present invention
includes or is coated with a drug coating according to the present
invention. In particular, a dosage form according to the present
invention includes a core coated by a drug coating of the present
invention. The core included in a dosage form according to the
present invention can be formed using any material or device
suitable for administration to an intended subject. For example,
the core included in a dosage form of the present invention may
includes a pill, a tablet or a capsule, and in preferred
embodiments the pill, tablet or capsule included in the core is
configured or formulated to provided controlled release of one or
more drugs. Where the dosage form of the present invention includes
a core the provides controlled release of one or more drugs, the
dosage form according to the present invention can be configured
and formulated to provide the combined benefits of an immediate
release dosage form and a controlled release dosage form.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 provides a graph illustrating the dissolution rate of
acetaminophen (APAP) from a drug coating according to the present
invention compared to the dissolution rate of APAP from a
commercially available Vicodin.RTM. tablet.
FIG. 2 provides a graph illustrating the dissolution rate of
hydrocodone bitartrate (HBH) from a drug coating according to the
present invention compared to the dissolution rate of HBH from a
commercially available Vicodin.RTM. tablet.
FIG. 3 provides a graph illustrating the ratio of APAP to HBH
released from drug coatings according to the present invention,
where the release ratio is determined by evaluating the dissolution
profiles of APAP and HBH based on mass balance.
FIG. 4 provides a graph illustrating the dissolution rate of APAP
from two different drug coatings according to the present invention
compared to the dissolution rate of APAP from a commercially
available NORCO.RTM. tablet.
FIG. 5 provides a graph illustrating the dissolution rate of APAP
from three different drug coatings according to the present
invention compared to the dissolution rate of APAP from a
commercially available NORCO.RTM. tablet.
DETAILED DESCRIPTION OF THE INVENTION
In one aspect, the present invention is directed to an aqueous drug
coating. A drug coating according to the present invention can be
formed from an aqueous coating formulation and includes an
insoluble drug and a water soluble, film-forming agent. Though each
embodiment of a drug coating according to the present invention
includes an insoluble drug, a drug coating according to the present
invention may also include an insoluble drug in combination with a
soluble drug. Moreover, a drug coating according to the present
invention may incorporate, for example, two or more insoluble
drugs, an insoluble drug in combination with one or more soluble
drugs, or two or more insoluble drugs in combination with one or
more soluble drugs. The total amount of drug included in a drug
coating according to the present invention ranges from about 85 wt
% to about 97 wt %, and in preferred embodiments, the total amount
of drug included in a drug coating of the present invention ranges
from about 90 wt % to about 93 wt %.
Even where the drug coating of the present invention includes only
insoluble drug material, the one or more insoluble drugs can
account for up to about 97 wt % of the drug coating. In preferred
embodiments, the drug coating of the present invention includes
from about 85 wt % to about 97 wt % insoluble drug, with coatings
exhibiting an insoluble drug loading of about 90 wt % to about 93
wt % being particularly preferred. If two or more insoluble drugs
are included in a drug coating according to the present invention,
the relative amounts of each insoluble drug can vary, depending on
the nature of the insoluble drugs used. Moreover, the relative
amounts of two or more insoluble drugs included in a drug coating
according to the present invention can be adjusted, as necessary,
to achieve a desired therapeutic effect.
Where a drug coating according to the present invention includes
one or more insoluble drugs in combination with one or more soluble
drugs, the relative amounts of the soluble and insoluble drugs
included in the coating can vary, depending on the nature of the
drug materials, and can be adjusted to achieve a desired
therapeutic effect. The total amount of soluble drug included in a
drug coating according to the present invention that incorporates
both soluble and insoluble drugs preferably ranges from about 0.01
wt % to about 25 wt %, with drug coatings including about 0.5 wt %
to about 15 wt % soluble drug being more preferred, and drug
coatings including about 1 wt % to about 3 wt % soluble drug being
most preferred. The total amount of insoluble drug included in a
drug coating according to the present invention that incorporates
both soluble and insoluble drugs preferably ranges from about 60 wt
% to about 96.99 wt %, with drug coatings including about 75 wt %
to about 89.5 wt % insoluble drug being more preferred, and drug
coatings including about 89 wt % to about 90 wt % insoluble drug
being most preferred.
A wide range of insoluble drugs may be incorporated into a drug
coating according to the present invention. In one embodiment, the
insoluble drug included in a drug coating according to the present
invention may be a non-steroidal anti-inflammatory drug, with
acetaminophen or ibuprofen being particularly preferred insoluble
drugs. Preferably, the insoluble drug included in a drug coating of
the present invention exhibits solubility characteristics similar
those of acetaminophen at 25.degree. C. or to those of ibuprofen at
25.degree. C.
A variety of different soluble drugs can also be used to create a
drug coating according to the present invention. In one embodiment,
the soluble drug included in a drug coating according to the
present invention is an opioid drug, with hydrocodone, oxycodone,
hydromorphone, oxymorphone, and methadone being particularly
preferred soluble drugs. Where the drug coating of the present
invention includes a soluble drug, the soluble drug included in the
drug coating preferably exhibits solubility that is at least as
great as that of hydrocodone bitartrate at 25.degree. C.
The film-forming agent included in a drug coating according to the
present invention is water soluble and accounts for about 3 wt % to
about 15 wt % of the drug coating, with drug coatings having about
7 wt % to about 10 wt % film-forming agent being preferred. The
film-forming agent included in a drug coating according to the
present invention is water soluble and preferably works to
solubilize insoluble drug included in the drug coating. In
addition, the film-forming agent included in a drug coating
according to the present invention may be chosen such that the
film-forming agent forms a solid solution with one or more
insoluble drugs included in the drug coating. It is believed that
drug loading and film forming characteristics of a drug coating
according to the present invention are enhanced by selecting a
film-forming agent that forms a solid solution with at least one of
the one or more insoluble drugs included in the drug coating. A
drug dissolved at the molecular level within the film-forming agent
(a solid solution) is also expected to be more readily bioavailable
because, as the drug coating breaks down or dissolves, the drug is
released into the gastrointestinal tract and presented to the
gastrointestinal mucosal tissue as discrete molecules.
In a preferred embodiment, the film-forming agent included in drug
coating according to the present invention is a film-forming
polymer or a polymer blend including at least one film-forming
polymer. Polymer materials used as the film-forming agent of a drug
coating of the present invention are water soluble. Examples of
water soluble polymer materials that may be used as the
film-forming polymer of a drug coating according to the present
invention include, but are not limited to, hydroxypropylmethyl
cellulose ("HPMC"), low molecular weight HPMC, hydroxypropyl
cellulose ("HPC") (e.g., Klucel.RTM.), hydroxyethyl cellulose
("HEC") (e.g., Natrasol.RTM.), copovidone (e.g., Kollidon.RTM. VA
64), and PVA-PEG graft copolymer (e.g., Kollicoat.RTM. IR), and
combinations thereof. A polymer blend or mixture may be used as the
film forming agent of the present invention in order to achieve a
drug coating having characteristics that may not be achievable
using a single film-forming polymer in combination with the drug or
drugs to be included in the drug coating. For example, blends of
HPMC and copovidone provide a film-forming agent that allows the
formation of drug coatings that not only exhibit desirable drug
loading characteristics, but also provide coatings that are
aesthetically pleasing and exhibit desirable physical
properties.
A drug coating according to the present invention may also include
a viscosity enhancer. Because the drug coating of the present
invention is an aqueous coating that includes one or more insoluble
drugs, the drug coating of the present invention is typically
coated from an aqueous suspension formulation. In order to provide
a drug coating with substantially uniform drug distribution from a
suspension formulation, however, the suspension formulation should
provide a substantially uniform dispersion of the insoluble drug
included in the coating. Depending on the relative amounts and
nature of the film-forming agent and the one or more drugs included
in a drug coating according to the present invention, a viscosity
enhancer may be included in a drug coating according to the present
invention to facilitate the creation of a coating formulation that
exhibits sufficient viscosity to provide a substantially uniform
drug dispersion and facilitates the production of a drug coating
according to the present invention having a substantially uniform
distribution of insoluble drug. A viscosity enhancer included in a
drug coating according to the present invention is preferably
water-soluble and can be a film-forming agent. Examples of
viscosity enhancers that may be used in a drug coating according to
the present invention include, but are not limited to, HPC (e.g.,
Klucel.RTM.), HEC (e.g., Natrasol.RTM.), Polyox.RTM. water soluble
resin products, and combinations thereof.
The precise amount of viscosity enhancing material included in a
drug coating according to the present invention will vary,
depending on the amounts and type of film-forming polymer and drug
materials to be used in the drug coating. However, where included
in a drug coating according to the present invention, a viscosity
enhancer will typically account for 5 wt %, or less, of the drug
coating. Preferably, a drug coating according to the present
invention includes 2 wt %, or less, viscosity enhancer, and in
particularly preferred embodiments, the drug coating according to
the present invention includes 1 wt %, or less, viscosity
enhancer.
The drug coating of the present invention may also include a
disintegrating agent that increases the rate at which the drug
coating disintegrates after administration. Because the drug
coating of the present invention typically includes a large amount
of insoluble drug, the drug coating may not break down or
disintegrate as rapidly as desired after administration. A
disintegrating agent included in a coating according to the present
invention is a water swellable material that works to structurally
compromise the coating as the disintegrating agent absorbs water
and swells. Disintegrating agents that may be used in a drug
coating according to the present invention include, but are not
limited to modified starches, modified cellulose, and cross-linked
polyvinylpyrrolidone materials. Specific examples of disintegrating
agents that may be used in the drug coating of the present
invention and are commercially available include Ac-Di-Sol.RTM.,
Avicel.RTM., and PVP XL-10. Where included in a drug coating
according to the present invention, a disintegrating agent
typically accounts for up to about 6 wt % of the coating, with
coatings incorporating from about 0.5 wt % to about 3 wt % being
preferred and coatings incorporating from about 1 wt % to about 3
wt % being particularly preferred.
The drug coating according to the present invention may also
include a surfactant to increase the rate at which the drug coating
dissolves or erodes after administration. The surfactant serves as
a "wetting" agent that allows aqueous liquids to more easily spread
across or penetrate the drug coating. Surfactants suitable for use
in a drug coating according to the present invention are preferably
solid at 25.degree. C. Examples of surfactants that may be used in
a drug coating of the present invention include, but are not
limited to, surface active polymers, such as Poloxamer and
Pluronic.RTM. surfactants. Where a surfactant is included in a drug
coating according to the present invention, the surfactant will
typically account for up to about 6 wt % of the drug coating, with
drug coatings including about 0.5 wt % to about 3 wt % surfactant
being preferred, and drug coatings including about 1 wt % to about
3 wt % surfactant being particularly preferred.
In one embodiment of the drug coating of the present invention, the
film-forming agent includes a polymer blend formed of copovidone
and HPMC. Where such a polymer blend is used as the film-forming
agent of the drug coating of the present invention, the amounts of
copovidone and HPMC may vary, as desired, to achieve a drug coating
having desired physical and drug-loading characteristics. However,
where the film-agent included in a drug coating according to the
present invention is formed of a blend of copovidone and HPMC, the
copovidone and HPMC are preferably included at a wt/wt ratio about
0.6:1 to about 0.7:1 copovidone to HPMC, with a wt/wt ratio of
1:1.5 being most preferred. Blends of HPMC and copovidone provide
drug coatings that are aesthetically pleasing and are believed to
be sufficiently robust to withstand further processing and an
extended shelf life. Moreover, it is believed that copovidone can
work to solubilize insoluble drug included in a drug coating
according to the present invention, providing a drug coating that
includes a solid solution of insoluble drug.
In another embodiment, the drug coating of the present invention
includes a blend of HPMC and copovidone as the film-forming agent,
and a non-steroidal anti-inflammatory drug (NSAID) as an insoluble
drug. NSAIDs that may be included in a drug coating according to
the present invention include, but are not limited to, ibuprofen,
acetaminophen and naproxen. NSAIDs are widely used as analgesics,
anti-inflammatories, and anti-pyretics, and such compounds can be
combined with a variety of different soluble drugs to obtain
multi-symptom relief from a variety of different ailments. For
example, a drug coating according to the present embodiment may
include an NSAID in combination with one or more soluble
analgesics, antihistamines or antitussive, or antinausea
agents.
In yet another embodiment, the drug coating of the present
invention includes a blend of HPMC and copovidone as the
film-forming agent, an insoluble NSAID, and a soluble narcotic
drug, such as an opiate or opioid drug. In a specific example of
such an embodiment, the drug coating includes an opioid drug, such
as hydrocodone. A dosage form that includes the combination of
acetaminophen or ibuprofen with an opiate or opioid drug provides a
combination of analgesic, anti-inflammatory, anti-pyretic, and
antitussive actions.
In even further embodiments, a drug coating according to the
present invention includes a blend of HPMC and copovidone as the
film-forming agent, an insoluble NSAID, a soluble narcotic drug,
such as an opiate or opioid drug, and a viscosity enhancing agent
or a disintegrating agent. In a specific example of such an
embodiment, the drug coating includes between about 1 wt % and
about 2 wt % of a viscosity enhancing agent, such as HPC. In
another example of such an embodiment, the drug coating includes
between about 0.5 wt % and about 3 wt % disintegrating agent, and
in yet another example of such an embodiment, the drug coating
includes between about 0.5 wt % and about 3 wt % of a
surfactant.
A drug coating according to the present invention is not only
capable of achieving high drug loading, but where the drug coating
according to the present invention includes two or more different
drugs, it has been found that a drug coating according to the
present invention provides releases the different drugs in amounts
that are directly proportional to the amounts of the drugs included
in the drug coating. This is true even where drugs exhibiting
drastically different solubility characteristics, such as
acetaminophen and hydrocodone bitartrate (HBH), are included in the
drug coating. In addition a drug coating according to the present
invention releases substantially all of the drug included therein.
Such performance characteristics facilitate reliable and
predictable drug delivery performance, and allow formulation of
drug coatings according to the present invention that deliver two
or more drugs at a wide range of different ratios.
In another aspect, the present invention is directed to a coating
formulation. A coating formulation according to the present
invention can be used to provide a drug coating according to the
present invention. The coating suspension of the present invention
includes the materials used to form a drug coating of the present
invention dissolved or suspended, depending on the material, within
one or more solvents or solutions. The one or more solvents
included in a coating suspension according to the present invention
are not organic solvents, and are preferably aqueous solvents.
Aqueous solvents that may be used in a coating suspension according
to the present invention include, but are not limited to, purified
water, pH adjusted water, acidified water, or aqueous buffer
solutions. In a preferred embodiment, the aqueous solvent included
in a coating suspension according to the present invention is
purified water USP. The coating formulation of the present
invention, therefore, is preferably an aqueous formulation and
avoids the potential problems and disadvantages that can result
from the use of organic solvents in formulating coating
compositions.
As a drug coating according to the present invention includes at
least one insoluble drug, the coating formulation of the present
invention is typically prepared as an aqueous suspension using any
suitable process, and in preferred embodiments the coating
formulation of the present invention is formulated to facilitate
production of drug coatings according to the present invention
through a known coating process, such as, for example, known pan
coating, fluid bed coating, or any other standard coating processes
suitable for providing a drug coating. Though the precise amount of
solvent used in a coating suspension according to the present
invention may vary depending on, for example, the materials to be
included in the finished drug coating, the desired coating
performance of the coating suspension and the desired physical
characteristics of the finished drug coating, a coating suspension
according to the present invention typically includes up to about
30 wt % solids content, with the remainder of the coating
suspension consisting of the desired solvent. A preferred
embodiment of a coating suspension of the present invention
includes about 80 wt % of a desired aqueous solvent and about 20 wt
% solids content. The coating suspension of the present invention
is formulated to exhibit a viscosity that is low enough to
facilitate spray coating of drug coating according to the present
invention, yet is high enough to maintain a substantially uniform
dispersion of the insoluble drug included in the coating suspension
during a coating process.
Because a coating formulation of the present invention is used to
create a drug coating according to the present invention, the
solids included in a coating suspension include materials useful in
forming a drug coating according to the present invention.
Therefore, the solids included in a coating suspension according to
the present invention include at least one insoluble drug and a
film-forming agent. The solids included in a coating suspension
according to the present invention may also include a viscosity
enhancer, a surfactant, or a disintegrating agent. As is true of a
drug coating according to the present invention, a coating
suspension according to the present invention may include two or
more insoluble drugs or one or more insoluble drugs in combination
with one or more soluble drugs.
In preparing a coating formulation according to the present
invention, the drug loaded into the coating formulation may be
provided in micronized form. By reducing the particle size of the
drug loaded into a coating formulation according to the present
invention, a more cosmetically smooth drug coating may be achieved.
In addition, by reducing the particle size of the drug material
loaded into a coating formulation according to the present
invention, the dissolution rate of the drug when released from the
drug coating prepared by the coating formulation may be improved,
particularly where the drug is an insoluble drug. In one embodiment
of the coating formulation of the present invention, the coating
formulation includes a micronized drug material exhibiting an
average particle size of less than 100 microns. In another
embodiment, the coating formulation of the present invention
includes a micronized drug material exhibiting an average particle
size of less than 50 microns, and in yet another embodiment, the
coating formulation of the present invention includes a micronized
drug material exhibiting an average particle size of less than 10
microns. Micronization of the drug material can be readily achieved
through processes well known in the art, such as, for example,
known bead milling, jet milling or microprecipitation processes,
and particle size can be measured using any conventional particle
size measuring technique, such as sedimentation field flow
fractionation, photon correlation spectroscopy or disk
cetrifugation.
The solids dissolved or suspended in a coating formulation
according to the present invention are loaded into the coating
formulation in the same relative amounts as are used in a drug
coating according to the present invention. For example, the drug
included in a coating formulation of the present invention accounts
for about 85 wt % to about 97 wt % of the solids loaded into the
coating formulation. In preferred embodiments, the drug included in
a coating formulation of the present invention accounts for about
90 wt % to about 93 wt % of the solids loaded into the coating
formulation. The film-forming agent included in a coating
formulation of the present invention accounts for about 3 wt % to
about 15 wt % of the solids loaded into the coating formulation,
and in preferred embodiments, the film-forming agent included in a
coating formulation of the present invention accounts for about 7
wt % to about 10 wt % of the solids loaded into the coating
formulation. Where included, a viscosity enhancer will typically
account for 5 wt %, or less, of the solids included in a coating
formulation of the present invention. Coating formulations wherein
the viscosity enhancer accounts for 2 wt %, or less, of the solids
are preferred, and in particularly preferred embodiments, a
viscosity enhancer included in a coating formulation of the present
invention accounts for 1 wt %, or less, of the solids included in
the coating formulation. If the coating to be formed by the coating
formulation is to include a disintegrating agent, the
disintegrating agent typically accounts for up to about 6 wt % of
the solids included in the coating formulation. In preferred
embodiments, a disintegrating agent will account for about 0.5 wt %
to about 3 wt % of the solids included in the coating formulation,
and in particularly preferred embodiments of a coating formulation
including a disintegrating agent, the disintegrating agent accounts
for about 1 wt % to about 3 wt % of the solids included in the
coating formulation. Where a surfactant is included in a drug
coating according to the present invention, the surfactant will
typically account for up to about 6 wt % of the solids included in
the coating formulation. Preferably, if a surfactant is included in
a coating formulation of the present invention, the surfactant will
account for about 0.5 wt % to about 3 wt % of the solids included
in the coating formulation, and in particularly preferred
embodiments of a coating formulation according to the present
invention that includes a surfactant, the surfactant accounts for
about 1 wt % to about 3 wt % of the solids included in the coating
formulation.
In yet another aspect, the present invention is directed to a
dosage form. A dosage form according to the present invention
includes a core coated by a drug coating according to the present
invention. The core included in a dosage form according to the
present invention can take on a variety of forms and may be
formulated to include one or drugs to be delivered after
dissolution or degradation of the drug coating. Where the core of a
dosage form includes one or more drugs, such drugs may be the same
as or different from the one or more drugs included in the drug
coating. Such flexibility in the design and formulation of the
dosage form of the present invention facilitates the creation of
dosage forms capable of delivering a wide range of drugs or
combinations of drugs to achieve a variety of different therapeutic
results.
In one embodiment, the core included in a dosage form according to
the present invention may be a pill, particle, pellet, bead, or
spheroid, such as nu pareil beads (collectively referred to simply
as "pills"). A pill used as a core in a dosage form of the present
invention may be formed of a variety of different materials.
Moreover, where the dosage form of the present invention includes a
core formed by a pill, the pill may be formulated to be free of
active agent or to include one or more active agents, as desired.
Materials useful for forming a pill to be used as a core in a
dosage form of the present invention include, but are not limited
to, polymer materials, such as plastic resins, inorganic
substances, such as silica, glass, hydroxyapatite, salts (e.g.,
sodium or potassium chloride, calcium or magnesium carbonate) and
the like, organic substances, such as activated carbon, acids
(e.g., citric acid, fumaric acid, tartaric acid, or ascorbic acid)
and the like, and saccharides and derivatives thereof. Particularly
suitable materials for forming a pill for use as a core in a dosage
form of the present invention include saccharides such as sugars,
oligosaccharides, polysaccharides and their derivatives, such as
glucose, rhamnose, galactose, lactose, sucrose, mannitol, sorbitol,
destrin, maltodextrin, cellulose, microcrystalline cellulose,
sodium carboxymethyl cellulose, starches (e.g., corn starch, rice
starch, potato starch, wheat starch, or tapioca starch) and the
like. Generally, the core forming materials discussed herein may be
used to form pills that are either free from of drug or include one
or more soluble or insoluble drugs, as desired.
In another embodiment, the dosage form of the present invention
includes a core formed using a tablet or capsule. The tablet or
capsule included in such an embodiment can take on virtually any
desired size or shape and may be manufactured using a wide range of
known materials. However, where the core of the dosage form of the
present invention includes a tablet or capsule, the table or
capsule is preferably manufactured of materials that are suitable
for oral delivery to a desired animal or human subject and tablet
or capsule is preferably sized and shaped to facilitate oral
delivery. For example, where the core includes a soft capsule or
"soft-cap" and the dosage form is intended for oral delivery to a
human subject, the soft-cap preferably exhibits a size ranging from
about 3 to about 22 minims, with 1 minim being equal to 0.0616 ml,
and the soft-cap may be provided, for example, in standard oval or
oblong shapes. In yet another example, where the core of a dosage
form of the present invention includes a hard capsule or "hard-cap"
and is intended for oral delivery to human subject, the hard-cap is
preferably provided in one of the various standard sizes designated
as (000), (00), (0), (1), (2), (3), (4), and (5). Although capsules
and tablets exhibiting standard shapes and sizes are presently
preferred due to their ready commercial availability, the core of a
dosage form of the present can be formed using tablets or capsules
of non-standard size or shape suited to a desired delivery
application.
Further, where a dosage form according to the present invention
includes a core formed using a tablet or capsule, the tablet or
capsule included in the core is preferably formulated or configured
to provide a controlled release dosage form. The subsequent coating
of such a core with a drug coating according to the present
invention formulated to provide the immediate release of one or
more drugs provides a dosage form exhibiting the performance
advantages of both an immediate release dosage form and a
controlled release dosage form. Controlled release dosage forms
that may be used to form the core of a dosage form of the present
invention include, but are not limited to, dosage forms well known
in the art, such as controlled release dosage forms that include a
tableted matrix, controlled release matrix dosage forms that
include a tableted matrix and are banded with one or more insoluble
bands to provided controlled release, and osmotically driven dosage
forms. Examples of controlled release dosage forms that may serve
as a core of a dosage form of the present invention include, but
are not limited to, the dosage forms described in U.S. Pat. Nos.
4,235,236, 4,278,087, 4,663,149, 4,777,049, 4,801,461, 4,854,470,
4,961,932, 5,023,088, 5,030,456, 5,221,536, 5,245,357, 5,512,299,
5,534,263, 5,614,578, 5,667,804, 5,830,502, 5,858,407, 5,906,832,
5,948,747, 6,020,000, 6,153,678, 6,174,547, 6,183,466, 6,245,357,
6,316,028, and 6,365,183; U.S. Patent Publications numbered
US2003-0198619, US2003-0232078, and US2002-0071863; PCT
Publications numbered WO 95/34285 and WO 04/02448; and PCT
Application numbered US04/24921 (not yet published), the contents
of each of which are incorporated herein in their entirety by
reference.
The drug coating included in a dosage form of the present invention
can be formed over the core included in the dosage form using
coating processes known in the art. Moreover, a drug coating
included in a dosage form of the invention can be formed using a
coating formulation as described herein. Suitable processes for
creating a drug coating in a dosage form of the present invention
include any standard coating process suitable for providing a drug
coating and include, but are not limited to, known pan coating and
fluid bed coating processes.
Though the dosage form of the present invention includes a core
coated by a drug coating according the present invention, the drug
coating is not necessarily the outermost coating of the dosage
form. For example, where desired, the drug coating included in a
dosage form according to the present invention may be coated with a
color coat or another finish coat to provide a final dosage form.
Alternatively, a drug coating included in a dosage form of the
present invention could be coated with another drug coating, or
even a coating designed to cause dissolution or degradation of the
drug coating at a specified location within the gastrointestinal
tract of an intended subject, such as an enteric coating, or at a
desired time post-administration. Moreover, even though the drug
coating included in a dosage form according to the present
invention is provided over a core, the drug coating need not be
immediately adjacent the core. Regardless of whether the core is
formed using a pill, a tablet, or a capsule, one or more material
layers may intervene between the drug coating and the core-forming
material or structure. Such intervening layers may be included to
facilitate better function of either the core forming material or
the drug coating. Alternatively, intervening material layers may
ease production of the drug coating or, where desirable, prevent
interaction between the core and the drug composition.
EXAMPLE 1
A drug coating according to the present invention was provided over
placebo dosage forms. The coating included 7.2 wt % film-forming
agent formed of a blend of HPMC E5 (supplied by Dow) and copovidone
(Kollidon.RTM. VA 64, supplied by BASF). The HPMC accounted for 4.3
wt % of the drug coating, and the Kollidon.RTM. VA 64 accounted for
2.9 wt % of the drug coating. Ibuprofen USP was the drug included
in the drug coating, and the ibuprofen USP accounted for 92.8 wt %
of the drug coating.
In order to form the drug coating, an aqueous coating formulation
was created using purified water USP as the solvent. The coating
formulation included a solids content of 24 wt % and a solvent
content of 76 wt %. The solids loaded into the coating formulation
were those that formed the finished drug coating, and the solids
were loaded in the coating formulation in the same relative
proportions as contained in the finished drug coating. The coating
formulation was mixed using standard procedures to achieve a
substantially uniform coating formulation. The coating formulation
was prepared as a 2,977.5 gram batch.
After forming the coating formulation, the drug coating was formed
over the placebo dosage forms using a Vector LDCS pan coater. The
pump included in the coater was a Masterflex.RTM. peristaltic pump
and the tubing used in the coater was Masterflex.RTM. 96410-16
tubing. The pan of the coater was charged with 1,800 g of the
coating formulation, and the drug coating was coated over the
placebo dosage forms under the conditions listed in Table 1. The
placebo dosage forms were processed in the coater for 4.5 hours,
resulting in the placebo dosage forms being coated with a drug
coating weighing about 165 mg, on average.
TABLE-US-00001 TABLE 1 Coating Conditions Pan Speed: 21 RPM Atom.
Air Pressure: 19 psi Gun-to-Bed Dist: 3.5'' Flow Rate: 12 g/min
Nozzle: 60100SS Air Cap: 120SS Exhaust Temp: 35.degree.
C.-45.degree. C. Pan Air Flow: 35-36 CFM
EXAMPLE 2
A drug coating according to the present invention was provided over
placebo dosage forms. The coating included 17.8 wt % film-forming
agent formed of a blend of HPMC E5 (supplied by Dow) and copovidone
(Kollidon.RTM. VA 64, supplied by BASF). The HPMC accounted for
10.7 wt % of the drug coating and the Kollidon.RTM. VA 64 accounted
for 7.1 wt % of the drug coating. The drug included in the coating
was ibuprofen USP, and the ibuprofen USP accounted for 82.2 wt % of
the drug coating.
In order to form the drug coating, an aqueous coating formulation
was created using purified water USP as the solvent. The coating
formulation included a solids content of 20 wt % and a solvent
content of 80 wt %. The solids loaded into the coating formulation
were those that formed the finished drug coating, and the solids
were loaded in the coating formulation in the same relative
proportions as contained in the finished drug coating. The coating
formulation was mixed using standard procedures to achieve a
substantially uniform coating formulation. The coating formulation
was prepared as a 3978.4 gram batch.
After forming the coating formulation, the drug coating was
provided over the placebo dosage forms using a Vector LDCS pan
coater. The pump included in the coater was a Masterflex.RTM.
peristaltic pump and the tubing used in the coater was
Masterflex.RTM. 96410-16 tubing. The pan of the coater was charged
with 1,800 g of the coating formulation, and the drug coating was
coated over the placebo dosage forms under the conditions listed in
Table 1. The placebo dosage forms were processed in the coater for
4.8 hours, resulting in the placebo dosage forms being coated with
a drug coating weighing about 188 mg, on average.
EXAMPLE 3
A drug coating according to the present invention was provided over
placebo dosage forms. The coating included 6.0 wt % film-forming
agent formed of a blend of HPMC E5 (supplied by Dow) and copovidone
(Kollidon.RTM. VA 64, supplied by BASF). The HPMC accounted for 3.6
wt % of the drug coating and the Kollidon.RTM. VA 64 accounts for
2.4 wt % of the drug coating. The drug coating also included HPC
(Klucel.RTM. MF) as a viscosity enhancer. The HPC accounted for 1.5
wt % of the drug coating. The drug included in the drug coating was
acetaminophen USP (APAP USP, supplied by BASF as a fine powder),
and the APAP USP accounted for 92.5 wt % of the drug coating.
In order to form the drug coating, an aqueous coating formulation
was prepared using purified water USP as the solvent. The coating
formulation included a solids content of 20 wt % and a solvent
content of 80 wt %. The solids loaded into the coating formulation
were those that formed the finished drug coating, and the solids
were loaded in the coating formulation in the same relative
proportions as included in the finished drug coating. The coating
formulation was mixed using standard procedures to achieve a
substantially uniform coating formulation.
The drug coating was formed over the placebo dosage forms using a
Vector LDCS pan coater. The pump included in the coater was a
Masterflex.RTM. peristaltic pump, and the tubing used in the coater
was Masterflex.RTM. 96410-16 tubing. The pan of the coater was
charged with 1,800 g of the coating formulation, and the drug
coating was coated over the dosage forms under the conditions
listed in Table 1. The placebo dosage forms were processed in the
coater for 3.75 hours, resulting in the placebo dosage forms being
coated with a drug coating weighing about 183 mg, on average.
EXAMPLE 4
A drug coating according to the present invention was provided over
placebo dosage forms. The coating included 6.6 wt % film-forming
agent formed of a blend of HPMC E5 (supplied by Dow) and copovidone
(Kollidon.RTM. VA 64, supplied by BASF). The HPMC accounted for
3.95 wt % of the drug coating and the Kollidon.RTM. VA 64 accounted
for 2.65 wt % of the drug coating. The drug coating also included
HPC (Klucel.RTM. MF) as a viscosity enhancer. The HPC accounted for
1.0 wt % of the drug coating. An insoluble drug and a soluble drug
were included in the drug coating, with the two drugs accounting
for 92.4 wt % of the drug coating. The insoluble drug included in
the coating was APAP USP (supplied by BASF as a fine powder), which
accounted for 90 wt % of the drug coating, and the soluble drug
included in the coating was hydrocodone bitartrate (HBH), which
accounted for 2.4 wt % of the drug coating.
In order to form the drug coating, an aqueous coating formulation
was created using purified water USP as the solvent. The coating
formulation included a solids content of 20 wt % and a solvent
content of 80 wt %. The solids loaded into the coating formulation
were those that formed the finished drug coating, and the solids
were loaded in the coating formulation in the same relative
proportions as contained in the finished drug coating. The coating
formulation was mixed using the procedure outlined in Table 3 to
obtain a substantially uniform coating formulation. The coating
formulation was prepared as a 4,000 gram batch.
After forming the coating formulation, the drug coating was
provided over the placebo dosage forms using a Vector LDCS pan
coater. The pump included in the coater was a Masterflex.RTM.
peristaltic pump and the tubing used in the coater was
Masterflex.RTM. 96410-16 tubing. The pan of the coater was charged
with 1,800 g of the coating formulation, and the drug coating was
coated over the placebo dosage forms under the conditions listed in
Table 1 until a coating of about 200 mg (average coating weight of
199.7 mg) was achieved.
TABLE-US-00002 TABLE 3 Coating Formulation Preparation Vessel I
Tare the Vessel and turn mixer on. Charge 1/3 water into the
vessel. While mixing, slowly charge the HPC into the vessel.
Continue mixing until the material is totally dissolved. Vessel II
Tare the vessel, charge 3/4 of water required into the vessel.
While mixing, slowly charge the Copovidone into the vessel.
Continue mixing until the material is dissolved. While mixing,
slowly charge the HPMC into the vessel. Continue mixing until the
material is dissolved. Transfer the Vessel I solution into the
Vessel II. Mix until a clear solution results. If including a
disintegrant or a surfactant, add disintegrant or surfactant while
mixing. Mix until the solution is homogeneous. While mixing, slowly
charge the insoluble drug (e.g., APAP or ibuprofen) into the mixing
vessel. Continue mixing until no lumps are present. Mix for at
least two hours before use. Determine the net amount of drug
coating formulation prepared. Continue mixing until the required
amount of drug coating formulation is applied. Do not allow a
vortex to form.
EXAMPLE 5
The dissolution rates of both APAP and HBH from the drug coating
prepared according to Example 4 was evaluated and compared with the
dissolution rates provided by Vicodin.RTM. tablets. USP Type II
equipment was used to evaluate the dissolution rates from the
exemplary drug coating and from the Vicodin.RTM. tablets. As can be
seen by reference to FIG. 1 and FIG. 2, the dissolution rates of
both APAP and HBH from the exemplary drug overcoat were comparable
to those provided by the Vicodin.RTM. tablets, with the t.sub.90 of
the APAP and HBH from the exemplary drug coating and from the
Vicodin.RTM. tablets occurring within 30 minutes.
EXAMPLE 6
The dissolution profiles of APAP and HBH from drug coatings
according to the present invention were evaluated based on mass
balance. The target release ratio of APAP:HBH from the drug coating
was 34:1. Three different lots of dosage forms having coatings
according to present invention were evaluated. The results of such
evaluation are provided in FIG. 3, and as can be seen from FIG. 3,
the drug coatings according to the present invention provided
desirable APAP and HBH release performance, with the drug coatings
in each lot releasing the APAP and HBH at or very near the targeted
release ratio.
EXAMPLE 7
The dissolution rates of APAP from four different drug coatings
according to the present invention were compared to the dissolution
rate of APAP from a commercially available NORCO.RTM. tablet. The
formulations of each of the four different drug coatings are
provided in Table 2. HBH was included in Table 2 for calculation
purposes only. The HBH was not included in any of the four coating
formulations prepared in this Example.
In order to form each of the four different drug coatings, four
different aqueous coating formulations were prepared using purified
water USP as the solvent. Each of the four coating formulations
included a solids content of 20 wt % and a solvent content of 80 wt
%. Each of the four coating formulations was loaded with the solids
used to form one of the four different coating formulations. The
coating formulations were mixed using procedure outlined in Table 3
to achieve substantially uniform coating formulations.
After forming the coating formulations, the four drug coatings were
provided over the placebo dosage forms using a Vector LDCS pan
coater. The pump included in the coater was a Masterflex.RTM.
peristaltic pump and the tubing used in the coater was
Masterflex.RTM. 96410-16 tubing. During each coating process, the
pan of the coater was charged with 1,800 g of the desired coating
formulation. The four different drug coatings were coated over the
placebo dosage forms under the conditions listed in Table 1 until
coatings provided the average weight gains detailed in Table 2.
In order to evaluate the dissolution rate of APAP from each of the
four different coatings and from the NORCO.RTM. tablet, a USP Type
II apparatus was used. The media used was 900 ml of acidified water
maintained at 37.degree. C., and the stir rate was 50 rpm. The
amount of APAP present in the media was measured at 5-minute
intervals over a period of 90 minutes using a standard UV assay
technique.
The results of the dissolution testing are shown in FIG. 4 and FIG.
5. As can be seen by reference to FIG. 4 and FIG. 5, the inclusion
of a surfactant or a disintegrating agent in a drug coating
according to the present invention can provide measurable
improvements in the rate at which drug is released from the drug
coating. In the case of the disintegrating agent Ac-Di-Sol.RTM.,
increasing the amount of Ac-Di-Sol.RTM. in the drug coating can
provide an increase in the rate at which drug is dissolved from the
coating, with the drug coating that includes 3.0 wt %
Ac-Di-Sol.RTM. providing a dissolution rate approaching that
provided by the NORCO.RTM. tablet.
TABLE-US-00003 TABLE 2 Drug Overcoat Formulations (Example 7)
Formulation (wt %) No Sufactant/ 1.5% 3.0% Materials Code No
Disintegrant Disentegrant Surfactant Disentegrant APAP 0012590
90.00 90.00 90.00 88.00 HBC 0011334 2.40 2.40 2.40 2.40 (For
Calculation Purposes Only) Copovidone 0011445 2.65 2.04 2.04 2.24
HPMC 2910 0001634 3.95 3.06 3.06 3.36 HPC 0000614 1.00 1.00 1.00
1.00 Ac-Di-Sol 80142 -- 1.50 -- 3.00 Poloxamer 188 4304 -- -- 1.50
-- Weight Gain 199.7 196.7 194.4 196.6 Total APAPDose 180 177 175
173
EXAMPLE 8
A drug coating according to the present invention including a
surfactant was formed over placebo dosage forms. The coating
included 5.1 wt % film-forming agent formed of a blend of HPMC 2910
and copovidone (Kollidon.RTM. VA 64, supplied by BASF). The HPMC
accounted for 3.06 wt % of the drug coating and the Kollidon.RTM.
VA 64 accounted for 2.04 wt % of the drug coating. The drug coating
also included HPC (Klucel.RTM. MF) as a viscosity enhancer, and
Poloxamer 188 as a surfactant. The HPC accounted for 1.0 wt % of
the drug coating, and the Poloxamer accounted for 1.5 wt % of the
drug coating. An insoluble drug and a soluble drug were included in
the drug coating, with the two drugs accounting for 92.4 wt % of
the drug coating. The insoluble drug included in the coating was
APAP USP (supplied by BASF as a fine powder), which accounted for
90 wt % of the drug coating, and the soluble drug included in the
coating was HBH, which accounted for 2.4 wt % of the drug
coating.
In order to form the drug coating, an aqueous coating formulation
was created using purified water USP as the solvent. The coating
formulation included a solids content of 20 wt % and a solvent
content of 80 wt %. The solids loaded into the coating formulation
were those that formed the finished drug coating, and the solids
were loaded in the coating formulation in the same relative
proportions as contained in the finished drug coating. The coating
formulation was mixed using the procedure outlined in Table 3 to
achieve a substantially uniform coating formulation.
After forming the coating formulation, the drug coating was
provided over the placebo dosage forms using a Vector LDCS pan
coater. The pump included in the coater was a Masterflex.RTM.
peristaltic pump and the tubing used in the coater was
Masterflex.RTM. 96410-16 tubing. The pan of the coater was charged
with 1,800 g of the coating formulation, and the drug coating was
coated over the placebo dosage forms under the conditions listed in
Table 1 until a drug coating of about 200 mg (average coating
weight of 194.4 mg) was achieved.
EXAMPLE 9
A drug coating according to the present invention including a
disintegrating agent was formed over placebo dosage forms. The
coating included 5.1 wt % film-forming agent formed of a blend of
HPMC 2910 and copovidone (Kollidon.RTM. VA 64, supplied by BASF).
The HPMC accounted for 3.06 wt % of the drug coating and the
Kollidon.RTM. VA 64 accounted for 2.04 wt % of the drug coating.
The drug coating also included HPC (Klucel.RTM. MF) as a viscosity
enhancer, and Ac-Di-Sol.RTM. as a disintegrating agent. The HPC
accounted for 1.0 wt % of the drug coating, and the Ac-Di-Sol.RTM.
accounted for 1.5 wt % of the drug coating. An insoluble drug and a
soluble drug were included in the drug coating, with the two drugs
accounting for 92.4 wt % of the drug coating. The insoluble drug
included in the coating was APAP USP (supplied by BASF as a fine
powder), which accounted for 90 wt % of the drug coating, and the
soluble drug included in the coating was HBH, which accounted for
2.4 wt % of the drug coating.
In order to form the drug coating, an aqueous coating formulation
was created using purified water USP as the solvent. The coating
formulation included a solids content of 20 wt % and a solvent
content of 80 wt %. The solids loaded into the coating formulation
were those that formed the finished drug coating, and the solids
were loaded in the coating formulation in the same relative
proportions as contained in the finished drug coating. The coating
formulation was mixed using the procedure outlined in Table 3 to
achieve a substantially uniform coating formulation.
After forming the coating formulation, the drug coating was
provided over the placebo dosage forms using a Vector LDCS pan
coater. The pump included in the coater was a Masterflex.RTM.
peristaltic pump and the tubing used in the coater was
MasterFlex.RTM. 96410-16 tubing. The pan of the coater was charged
with 1,800 g of the coating formulation, and the drug coating was
coated over the placebo dosage forms under the conditions listed in
Table 1 until a drug coating of about 200 mg (average coating
weight of 196.7 mg) was achieved.
EXAMPLE 10
A drug coating according to the present invention including a
disintegrating agent is prepared and coated onto a dosage form. The
coating includes 5.6 wt % film-forming agent formed of a blend of
HPMC 2910 and copovidone (Kollidon.RTM. VA 64, supplied by BASF).
The HPMC accounts for 3.36 wt % of the drug coating and the
Kollidon.RTM. VA 64 accounts for 2.24 wt % of the drug coating. The
drug coating also includes HPC (Klucel.RTM. MF) as a viscosity
enhancer, and Ac-Di-Sol.RTM. as a disintegrating agent. The HPC
accounts for 1.0 wt % of the drug coating, and the Ac-Di-Sol.RTM.
accounts for 3.0 wt % of the drug coating. An insoluble drug and a
soluble drug are included in the drug coating, with the two drugs
accounting for 90.4 wt % of the drug coating. The insoluble drug
included in the coating is APAP USP (supplied by BASF as a fine
powder), which accounts for 88.0 wt % of the drug coating, and the
soluble drug included in the coating is HBH, which accounts for 2.4
wt % of the drug coating.
An aqueous coating formulation is created using purified water USP
as the solvent. The coating formulation includes a solids content
of 20 wt % and a solvent content of 80 wt %. The solids loaded into
the coating formulation are those that form the finished drug
coating, and the solids are loaded in the coating formulation in
the same relative proportions will be exhibited in the finished
drug coating. The coating formulation is mixed using the procedure
outlined in Table 3 to achieve a substantially uniform coating
formulation.
After forming the coating formulation, the drug coating is provided
over the dosage forms using a Vector LDCS pan coater. The pump
included in the coater is any suitable pump, such as a
Masterflex.RTM. peristaltic pump, and the tubing used in the coater
is any suitable tubing, such as Masterflex.RTM. 96410-16 tubing.
The pan of the coater is charged with a desired amount of the
coating formulation, and the drug coating is coated over the dosage
forms under the conditions listed in Table 1 until a drug coating
of a desired weight is achieved.
EXAMPLE 11
A drug coating according to the present invention is provided over
a dosage form. The coating includes 7.0 wt % film-forming agent
formed of a blend of HPMC E5 (supplied by Dow) and copovidone
(Kollidon.RTM.VA 64, supplied by BASF). The HPMC accounts for 4.2
wt % of the drug coating, and the Kollidon.RTM. VA 64 accounts for
2.8 wt % of the drug coating. The drug coating includes an
insoluble drug and a soluble drug, with the total drug content of
93 wt %. The insoluble drug included in the coating is ibuprofen
USP, which accounts for 90 wt % of the drug coating, and the
soluble drug included in the coating is HBH, which accounts for 3
wt % of the drug coating.
To form the drug coating, an aqueous coating formulation is
prepared using purified water USP as the solvent. The coating
formulation includes a solids content of 25 wt % and a solvent
content of 75 wt %. The solids loaded into the coating formulation
are those that form the finished drug coating, and the solids are
loaded in the coating formulation in the same relative proportions
as will be exhibited in the finished drug coating. The coating
formulation is mixed using standard procedures to achieve a
substantially uniform coating formulation.
The drug coating is formed over the dosage forms using any suitable
coater, such as a Vector LDCS pan coater. The pump included in the
coater is any suitable pump, such as a Masterflex.RTM. peristaltic
pump, and the tubing used in the coater is any suitable tubing,
such as Masterflex.RTM. 96410-16 tubing. The pan of the coater is
charged with a desired amount of the coating formulation, and the
drug coating is coated over the placebo dosage forms under the
conditions listed in Table 1 until a drug coating of a desired
weight is achieved.
EXAMPLE 12
A drug coating according to the present invention is formed over a
dosage form. The coating includes 17.3 wt % film-forming agent
formed of a blend of HPMC E5 (supplied by Dow) and copovidone
(Kollidon.RTM. VA 64, supplied by BASF). The HPMC accounts for 10.4
wt % of the drug coating and the Kollidon.RTM. VA 64 accounts for
6.9 wt % of the drug coating. The drug coating includes an
insoluble drug and a soluble drug, with the total drug content of
82.7 wt %. The insoluble drug included in the coating is ibuprofen
USP, which accounts for 80 wt % of the drug coating, and the
soluble drug included in the coating is HBH, which accounts for 2.7
wt % of the drug coating.
To form the drug coating, an aqueous coating formulation is
prepared using purified water USP as the solvent. The coating
formulation includes a solids content of 20 wt % and a solvent
content of 80 wt %. The solids loaded into the coating formulation
are those that form the finished drug coating, and the solids are
loaded in the coating formulation in the same relative proportions
as will be exhibited in the finished drug coating. The coating
formulation is mixed using standard procedures to achieve a
substantially uniform coating formulation.
The drug coating is provided over the dosage forms using any
suitable coater, such as a Vector LDCS pan coater. The pump
included in the coater is any suitable pump, such as a
Masterflex.RTM. peristaltic pump, and the tubing used in the coater
is any suitable tubing, such as Masterflex.RTM. 96410-16 tubing.
The pan of the coater is charged with a desired amount of the
coating formulation, and the drug coating is coated over the dosage
forms under the conditions listed in Table 1 until a drug coating
of a desired weight is achieved.
EXAMPLE 13
A drug coating according to the present invention is provided over
a dosage form. The coating includes 5.85 wt % film-forming agent
formed of a blend of HPMC E5 (supplied by Dow) and copovidone
(Kollidon.RTM. VA 64, supplied by BASF). The HPMC accounts for 3.5
wt % of the drug coating and the Kollidon.RTM. VA 64 accounts for
2.35 wt % of the drug coating. The drug coating also includes HPC
(Klucel.RTM. MF) as a viscosity enhancer. The HPC accounts for 1.5
wt % of the drug coating. An insoluble drug and a soluble drug are
included in the drug coating, with the two drugs accounting for
92.65 wt % of the drug coating. The insoluble drug included in the
coating is acetaminophen, which accounts for 90 wt % of the drug
coating, and the soluble drug included in the coating is HBH, which
accounts for 2.65 wt % of the drug coating.
In order to form the drug coating, an aqueous coating formulation
is prepared using purified water USP as the solvent. The coating
formulation includes a solids content of 20 wt % and a solvent
content of 80 wt %. The solids loaded into the coating formulation
are those that form the finished drug coating, and the solids are
loaded in the coating formulation in the same relative proportions
as will be exhibited in the finished drug coating. The coating
formulation is mixed using the procedure outlined in Table 3 to
achieve a substantially uniform coating formulation.
The drug coating is formed over the dosage forms using any suitable
coater, such as a Vector LDCS pan coater. The pump included in the
coater is any suitably pump, such as a Masterflex.RTM. peristaltic
pump, and the tubing used in the coater may be any suitable tubing,
such as Masterflex.RTM. 96410-16 tubing. The pan of the coater is
charged with a desired amount of the coating formulation, and the
drug coating is coated over the dosage forms under the conditions
listed in Table 1 until a coating of desired weight is
achieved.
* * * * *
References